Pyridine and piperidine compounds and process of making same



Patented May 16, 1950 PYRIDINE AND PIPERIDINE COMPOUNDS AND FBOCESS FMAKING SAME Max Hartmann and Leandro Panizzon, Riehen, Switzerland,assignors to Ciba Pharmaceutical Products Inc., Summit, N. J., acorporation of N ew Jersey No Drawing. Application March 9, 1945, SerialNo. 581,971. In Switzerland January 19, 1944 Section 1, Public Law 690,August 8, 1946 Patent expires January 19, 1964 19 Claims. 1

According to this invention new pyridine and piperidine compounds areobtained by causing monoaryl-aceto-nitriles whose acetonitrile radicalcontains at least one hydrogen atom to react with nuclear halogenatedpyridines and piperidines in the presence of agents eliminating hydrogenhalide, if desired, replacing one hydrogen atom at the carbon atomlinked to the nitrile group by an alkyl radical, transforming thenitrile group in the compounds thus obtained into the carboxyl group orinto an ester or an amide group in one or several steps, if desired,converting the resulting pyridines into the corresponding piperidines bymeans of reducing agents and/or, if desired, further substituting thepyridine or piperidine compounds thus obtained at the ring nitrogenatom.

The monoaryl-acetonitrile used for the reaction may contain asubstituent in the methylene group of the acetonitrile radical and oneor several substituents in the aryl radical. Examples are:phenyl-acetonitrile, naphthyl-acetonitrile,a-phenyl-a-alky1-acetonitriles, such as a-phenyla-methyl-acetonitrile,S-methoxyphenyl-acetonitrile, 3:4-dimethoxyphenyl acetonitrile, 3z4-methylene dioxyphenyl acetonitrile. Nuclear halogenated pyridines andpiperidines are for example: 2-chloro-pyridine, i-chloro-pyridine, 1-methyl-B-chloro-piperidine. These may also contain further substituents.Thus 2-chloro-5-nitro-pyridine may be used as starting material. Thereaction is carried out preferably in inert solvents, such as forexample, ether, benzene, toluene and the like. For the elimination ofthe hydrogen halide there are preferably used sodium, potassium, lithiumas such or in the form of their amides, hydrides, alcoholates orhydrocarbon compounds, such as for example sodium amide, sodium hydride,potassium-tertiary butylate, po-

tassium-tertiary amylate, butyl-lithium, phenylsodium or phenyl-lithium.

If acetom'triles are obtained in this reaction which still contain ahydrogen atom at the carbon atom linked with the nitrile group, this canbe replaced by the corresponding alkyl radicals, for example by reactionwith alkyl halides, such as methyl, ethyl or diethylamino-ethyl chloridein the presence of agents eliminating hydrogen halide.

The acids and their amides are produced from thea-aryl-a-pyridyl-acetonitriles or a-QJYI-apiperidyl-acetonitrilesobtained by the reaction by the action of suitable hydrolyzing agents.The amides can also be produced from the acids or their derivatives suchas halides by the reaction with ammonia or amines. The esters areobtained from the nitriles, acids or amides with correspondingesterifying agents, such alcohols or derivatives thereof being alsouseful which contain basic groups.

The pyridine carboxylic acids or their amides and esters obtainedaccording to the present process can be converted into the correspondingpiperidine compounds by the action of such reducing agents as are knownfor the hydrogenation of the pyridine nucleus.

The further substitution at the ring nitrogen atom of the pyridines andpiperidines formed in the present process can take place in any stage ofthe reaction. The corresponding quaternary compounds can thus beproduced for example by reaction with alkyl-halides, alkylene-halides,aryl-sulfonic acid esters, dialkyl-sulfates or also arylalkyl-halides.It is also possible to obtain tertiary piperidines by starting frompiperidines which are not substituted at the ring nitrogen atom.

The compounds produced according to the present process possess valuablepsysiological properties and are to be used as medicaments or asintermediate products for the preparation of medicaments.

The following example illustrates the invention, but are not to beregarded as limiting it in any way:

Example grams of pulverized sodium amide are gradually added, whilestirring and cooling, to a solution of 117 g. of phenyl-acetonitrile and113 g. of 2-chloropyridine in 400 cc. of absolute toluene. The mixtureis then slowly heated to -120 C. and maintained at this temperature for1 hour. Water is added thereto after cooling, the toluene solution isshaken with dilute hydrochloric acid and the hydrochloric acid extractsare made alkaline with concentrated caustic soda solution. A solid massis separated thereby which is taken up in acetic ester and distilled,a-phenyla-pyridyI-(Z) -acetonitrile passing over at C. under 0.5 mm.pressure. When recrystallized from ethyl acetate it melts at 88-89" C.,the yield amounting to.l35 g.

In similar manner there are obtained ll-(smethoxy-phenyl) a. -pyridyl-(2) -acetonitrile of melting point 54-55 C. when starting from 3-methoxyphenyl-acetonitrile and 2-chloropyridine,a-(3Z4-d111'18th0XYDh8IlYl) a -pyridyl -(2) acetonitrile of boilingpoint 192-l95 C. under 0.2 mm. pressure when starting from3:4-dimethoxyphenyl-acetonitrile and 2-chloropyridine, a-(3z4- methylenedioxyphenyl) a -pyridyl -(2) acetonitrile of boiling point 170-180" C.under 0.15 mm. pressure when starting from 3:4-methylene-dioxyphenylacetonitrile and 2-chloropyridine, e-naphthyl (1) -a pyridyl -(2)acetonitrile of melting point 87 C. when starting from naphthyl-(l)-acetonitrile and 2-chloropyridine, aphenyl-a-methyl oz pyridyl- (2)-acetonitrile of boiling point 145-150 C. under 0.2 mm. pressure whenstarting from c-phenyl-e-methylaoetonitrile and 2-chloropyridine,a-phllYl-a-DYlidYl- (4) -acetonitrile of melting point 76-77 0. whenstarting from phenyl-acetonitrile and 4-chloropyridine,a-phenyl-aethyl-a-py1idyl- (4) -acetnitrile of boiling point 193 C.under 11 mm. pressure when starting from a-phenyl-a-ethylacetonitrileand 4-chloropyridine, and u-phenyla- [N -methyl-piperidyl- (3)l-acetonitrile of boiling point 140-145 C. under 0.2 mm. pressure whenstarting from phenyl-acetonitrile and N- methyl-3-chloropiperidine.

The indicated a-phenylor. -alkyl- 0: -pyridylacetonitriles can also beobtained by aikylation oi a-phenyl-a-pyridyl-acetonitrile with thecorresponding alkyl-halides in the presence of sodium amide.

100 g. of a-phenyl-a-pyridyI-(Z) acetomtrile are introduced into 400 cc.of concentrated sulfuric acid, allowed to stand overnight at roomtemperature, poured into ice and rendered a1- kaline with sodiumcarbonate. a-Phenyl-a-pyridyl-(2) -acetamide is precipitated therebywhich melts at 134 C. after recrystallization from ethyl acetate. Theyield amounts to 96 g. When treating this product on the water bath withdimethylsulfate in alcohol there is obtained the correspondingN-methyl-pyridinium-methosulfate of melting point 165 C. in good yield.

100 g. of the resulting a-phenyl-a-pyridyl-(2)- acetamide, whendissolved in 1 liter of methylalcohol and treated for 6 hours atwater-bath temperature with hydrogen chloride, and after concentrating,diluting with water and rendering alkaline with sodium carbonate, yield90 g. of the a-phenyI-a-pyridyI-(Z) -acetic acid methylester of meltingpoint 74-75 C. (from alcohol of 50 per cent. strength). Thecorresponding a-phenyl-apyridyl-(2) -acetic acid ethylester of boilingpoint 155-160 C. under 0.4 mm. pressure is obtained in similar mannerwhen carrying out the ester'ification in the presence of ethylalcohol.

These esters can also be obtained when subjecting directly thea-phenyl-a-pyridyl-(2) acetonitrile dissolved in the respective alcohol,instead of the amide, to the same treatment with hydrogen chloride atwater-bath temperature.

The a-phenyl-a-piperidyl-( 2) -acetic acid methylester of boiling point135-137 C. under 0.6 mm. pressure is obtained in theoretical yield byhydrogenation of 50 g. of a-phenyl-a-pyridyI-(Z) -acetic acidmethylester in glacial acetic acid in the presence of 1 g. of platinumcatalyst at room temperature, while taking up 6 hydrogen atoms. TheN-methyl derivative produced with formaldehyde and formic acid, boils at153 C. under 0.4 mm. pressure.

a-Phenyl-a-piperidyl-(2)-acetic acid methylester is also obtained in thefollowing manner: by hydrogenation of a-phenyl-a-pyridyl-(2)- acetamide,also with platinum catalyst, there is obtained the correspondinga-phenyl-a-piperidyb (2) -acetamide whose acetate, when recrystallizedfrom ethylacetate, melts at 158 C. By saponification with boilinghydrochloric acid this yields the a-PhGDYI-a-PiDEl'idYl- (2) acetic acidhydrochlo- 4 ride of decomposition point 248 C. The esteriflcation withmethyl alcohol yields the above named ester. The correspondingethylester forms a hydrochloride of melting point 173 C. and an N-methyl derivative of boiling point 138-140 C. under 0.4 mm. pressure.The n-propylester yields a hydrochloride of melting point 181 C. and aN- methyl-derivative of boiling point 140 C. under 0.3 mm. pressure.

The following amides and esters have been produced in similar manner:

a-Phenyl-a-pyrid'yl-(4)-acetamide, of melting point 154 C.;

a-Phenyl-a-pyridyl- (2) -a-methyl-acetamide, of

melting point 130 C.;

a Phenyl a. pyridyl- (2) -a-ethyl-acetamide, of

melting point 108 C.

a Phenyl-a-piperidyI-(Z) -a-ethyl-acetamlde, of

melting point 151-152 C.;

a-Phenyl-a-pyridyl-(4)-acetic acid methylester of boiling point C. under0.2 mm. pressure;

oc-PhGllYl-a-DlDGIidYl-(4) -acetic acid methylester of boiling point 145C. under 0.2 mm. pressure;

a Phenyl a N -methylpiperidyl-(4) -acetic acid methylester of meltingpoint 63 C.;

a Phenyl a-pyridyI-(Z) -acetic acid-fi-diethyL aminoethylester ofboilingpoint -163 under 0.2 mm. pressure;

a Phenyl a-piperidyl- (2) -aceticacid-p-diethylaminoethylester-hydrochloride of melting point C.

Instead of the N-methyl-derivatives other N- alkyl-derivatives may beobtained, for instance with ethylbromide, alkylchloride and otheralkylating agents.

What We claim is:

1. A compound of the-formula wherein Ar stands for a member selectedfrom the group consisting of monocyclic aryl and condensed bicyclicaryl, X represents a member selected from the group consisting ofhydrogen and lower alkyl, Pe stands for a member selected from the groupconsisting of pyridine and piperidine radicals a nuclear carbon atom ofwhich is directly connected with C, and R stands for a member selectedfrom the group consisting of the nitrile group and esterified andamidated carboxyl groups.

2. A compound of the formula wherein Ar stands for phenyl, X represents"a member selected from the group consisting of'hydrogen and loweralkyl, Pe stands for a member selected from the group consisting ofpyridine and piperidine radicals a nuclear carbon atom of which isdirectly connected with- C and R stands for a member selected from thegroup consisting of the nitrile group, esterified andamidated carboxylgroups.

3. a-Phenyl-a-pyridyl-acetic acid esters.

4. a-PhenyI-a-pyridyl-(Z) -acetic acid esters.

5. The a phenyl a-PYlidYl-(2) -acetic acid methylester.

6. a-Phenyl-a-piperidyl-acetic acid esters.

7. a-Phenyl-a-piperidyl-(iz)-acetic acid esters.

8. The a-phenyI-a-piperidyI-(Z) -acetic acid methylester.

9. A process for the manufacture of a member selected from the groupconsisting of pyridine and piperidine compounds, comprising treating amonoaryl-aceto-nitrile whose aceto-nitrile radical contains at least onehydrogen atom with a member selected from the group consisting ofnuclear halogenated pyridines and piperidines in the presence of anagent eliminating hydrogen halide.

10. A process for the manufacture of a member selected from the groupconsisting of pyridine and piperidine compounds, comprising treating amonophenyl-aceto-nitrile whose aceto-nitrile radical contains at leastone hydrogen atom with a member selected from the group consisting ofnuclear halogenated pyridines and piperidines in the presence of anagent eliminating hydrogen halide.

11. A process according to claim 10, wherein the reaction is carried outin the presence of sodium amide.

12, A process according to claim 9, wherein the nitrile group of theobtained a-aryl-a-pyridylaceto-nitrile is converted into an ester groupas additional step.

13. A process according to claim 10, wherein the nitrile group of theobtained a-phenyl-apyridyl-aceto-nitrile is converted into an estergroup as additional step.

14. A process according to claim 9, wherein the nitrile of the obtaineda-aryl-a-pyridyl-acetonitrile is converted into an ester group and thethus obtained ester is treated with hydrogen in the presence of acatalyst of the platinum group as additional steps.

15. A process according to claim 9, wherein the nitrile of the obtaineda-phenyl-a-pyridyl-aceto- 6 nitrile is converted into an ester group andthe thus obtained ester is treated with hydrogen in the presence of a.catalyst of the platinum group as additional steps.

16. A process for the manufacture of a-phenyla-pyridy1-(2)-acetic acidmethyl ester, comprising treating a-phenyI-a-pyridyI-(Z)-acetonitrilewith methylalcohol in the presence of water and hydrogen chloride.

17. A process for the manufacture of a-phenyla-IfiIJQIidYl-(Z) -aceticacid methylester, comprising treating a-phenyl-u-pyridyl-(2)-acetic acidmethylester with hydrogen in the presence of platinum catalyst.

18. a Phenyl-a- [N -alkyl-piperidyl-(2) ]-acetic acid esters.

19. a. Phenyl a [N methyl-piperidyl-(Z) lacetic acid methylester.

MAX HARTMANN. LEANDRO PANIZZON.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,268,108 Collie Dec. 30, 1941FOREIGN PATENTS Number Country Date 710,227 Germany 1941 552,065 GreatBritain 1943 OTHER REFERENCES Whitmore: J. Amer. Chem. 800., May 1944.PP. 725-731.

1. COMPOUND OF THE FOMRULA 